..Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays...

The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein

..These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans...

..Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable...

BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character

..Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures...

Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics

..In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration...

Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics